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PMID:11788820
| Citation |
Gervais, FG, Singaraja, R, Xanthoudakis, S, Gutekunst, CA, Leavitt, BR, Metzler, M, Hackam, AS, Tam, J, Vaillancourt, JP, Houtzager, V, Rasper, DM, Roy, S, Hayden, MR and Nicholson, DW (2002) Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi. Nat. Cell Biol. 4:95-105 |
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| Abstract |
In Huntington disease, polyglutamine expansion of the protein huntingtin (Htt) leads to selective neurodegenerative loss of medium spiny neurons throughout the striatum by an unknown apoptotic mechanism. Binding of Hip-1, a protein normally associated with Htt, is reduced by polyglutamine expansion. Free Hip-1 binds to a hitherto unknown polypeptide, Hippi (Hip-1 protein interactor), which has partial sequence homology to Hip-1 and similar tissue and subcellular distribution. The availability of free Hip-1 is modulated by polyglutamine length within Htt, with disease-associated polyglutamine expansion favouring the formation of pro-apoptotic Hippi-Hip-1 heterodimers. This heterodimer can recruit procaspase-8 into a complex of Hippi, Hip-1 and procaspase-8, and launch apoptosis through components of the 'extrinsic' cell-death pathway. We propose that Htt polyglutamine expansion liberates Hip-1 so that it can form a caspase-8 recruitment complex with Hippi. This novel non-receptor-mediated pathway for activating caspase-8 might contribute to neuronal death in Huntington disease. |
| Links |
PubMed Online version:10.1038/ncb735 |
| Keywords |
Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Apoptosis/physiology; Carrier Proteins/genetics; Carrier Proteins/metabolism; Caspase 8; Caspase 9; Caspases/genetics; Caspases/metabolism; Cells, Cultured; DNA-Binding Proteins; Enzyme Activation; Humans; Huntington Disease/enzymology; Huntington Disease/metabolism; Mice; Models, Molecular; Molecular Sequence Data; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Neurons/metabolism; Neurons/ultrastructure; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Protein Structure, Tertiary; Rats; Sequence Alignment; Tissue Distribution; Two-Hybrid System Techniques |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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